This proposal is a mentored training grant that combines research efforts with a didactic plan designed to provide a strong background in immunology, skin physiology/carcinogenesis and the team science approach necessary for the PI's future success as an independent investigator. The PI has a long-standing interest in the inflammatory and immune-related molecular mechanisms of skin disease and the research focus of this proposal investigates the role of Toll-Like Receptor 3 in skin homeostasis, injury and neoplasia. TLR3 is over- expressed within non-melanoma skin cancers (NMSC) and no study to date has examined whether activation of the TLR3 signaling pathway plays a role in protection or is involved in neoplasia initiation and progression. This proposal will use both in vitro and in vivo methodologies to test the overall hypothesis activation of the TLR3 signaling pathway induces injured keratinocytes to acquire cancer stem cell-like properties, which subsequently promotes tumorigenesis. In Aim 1, we will test the hypothesis that TLR3 signaling promotes changes in keratinocytes consistent with an epithelial-to-mesenchymal transition (EMT). In Aim 2, we will use both in vitro and in vivo models to test the hypothesis that TLR3 signaling plays a causal role in formation NMSC by UVB. This proposal challenges current research which focuses on pro-inflammatory role of TLR3 and highlights its likely function as an initiator of tumorigenesis. Our proposal is significant in that it will advance the field of skin biology by increasing our understanding of a link between innate immunity and skin tumorigenesis.